rs62508691
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP3PM5PM3_StrongPP4_ModeratePM2
This summary comes from the ClinGen Evidence Repository: The c.823C>T (p.Pro275Ser) variant in PAH is absent from all population databases, and is in the same codon as two other likely pathogenic variants. In silico algorithms agree on a damaging effect. It has been identified in trans with two independent pathogenic variants (R408W and c.669delC; PMID:20123475, 24705691), and a defect in BH4 metabolism was excluded as a cause of elevated phenylalanine in multiple patients. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, PM5, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229789/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.823C>T | p.Pro275Ser | missense_variant | 7/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.823C>T | p.Pro275Ser | missense_variant | 8/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.823C>T | p.Pro275Ser | missense_variant | 7/13 | 1 | NM_000277.3 | P1 | |
PAH | ENST00000307000.7 | c.808C>T | p.Pro270Ser | missense_variant | 8/14 | 5 | |||
PAH | ENST00000549247.6 | n.582C>T | non_coding_transcript_exon_variant | 1/6 | 2 | ||||
PAH | ENST00000635477.1 | upstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:3
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Dec 09, 2018 | The c.823C>T (p.Pro275Ser) variant in PAH is absent from all population databases, and is in the same codon as two other likely pathogenic variants. In silico algorithms agree on a damaging effect. It has been identified in trans with two independent pathogenic variants (R408W and c.669delC; PMID: 20123475, 24705691), and a defect in BH4 metabolism was excluded as a cause of elevated phenylalanine in multiple patients. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, PM5, PP3. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 20, 2023 | For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function. ClinVar contains an entry for this variant (Variation ID: 102853). This missense change has been observed in individual(s) with phenylketonuria (PMID: 32668217; BIOPKU http://www.biopku.org). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 275 of the PAH protein (p.Pro275Ser). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 07, 2018 | - - |
not provided Other:1
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at